Tissue fibrosis (scarring) is a leading cause of morbidity and mortality. Current treatments for fibrotic disorders, such as idiopathic pulmonary fibrosis, hepatic fibrosis and systemic sclerosis, target the inflammatory cascade, but they have been widely unsuccessful, largely because the mechanisms that are involved in fibrogenesis are now known to be distinct from those involved in inflammation (Wynn, T. 2004: Nat. Rev. Immunol. 4(8): pp. 583-594).
Repair of damaged tissues is a fundamental biological process that allows the ordered replacement of dead or injured cells during an inflammatory response, a mechanism that is crucial for survival. Tissue damage can result from several acute or chronic stimuli, including infections, autoimmune reactions and mechanical injury. The repair process involves two distinct stages: a regenerative phase, in which injured cells are replaced by cells of the same type and there is no lasting evidence of damage; and a phase known as fibroplasia or fibrosis, in which connective tissue replaces normal parenchymal tissue. In most cases, both stages are required to slow or reverse the damage caused by an injurious agent. However, although initially beneficial, the healing process can become pathogenic if it continues unchecked, leading to considerable tissue remodelling and the formation of permanent scar tissue. In some cases, it might ultimately cause organ failure and death. Fibrotic scarring is often defined as a wound-healing response that has gone awry (Wynn, T. 2004: Nat. Rev. Immunol. 4(8): pp. 583-594).
Fibroproliferative diseases are an important cause of morbidity and mortality worldwide. Fibrotic changes can occur in various vascular disorders, including cardiac disease, cerebral disease and peripheral vascular disease, as well as in all the main tissues and organ systems, including the skin, kidney, lung, eye, bladder, heart, joints, intestinal tissues, connective tissue, reproductive tissue, bone tissue and liver. Fibrosis is a troubling problem for an increasing number of individuals and is a common pathological sequela of many persistent inflammatory diseases, such as idiopathic pulmonary fibrosis, progressive kidney disease and liver cirrhosis (Wynn, T. 2004: Nat. Rev. Immunol. 4(8): pp. 583-594).
The United States government estimates that 45% of deaths in the United States can be attributed to fibrotic disorders. Fibrosis affects nearly all tissues and organ systems. Interstitial Lung Disease (ILD) characterised by pulmonary inflammation and fibrosis is an example of disorders in which fibrosis is a major cause of morbidity and mortality. ILD is known to have a number of causes such as sarcoidosis, silicosis, collagen vascular diseases, systemic sarcoderma. However, the causes of the common type of ILD such as idiopathic pulmonary fibrosis are unknown. Other organ fibrotic disorders include liver cirrhosis; liver fibrosis resulting from chronic hepatitis B and C infection; kidney disease; heart disease; diseases of the eye such as macular degeneration, and retinal and vitreal retinopathy; systemic and local scleroderma; keloids and hypertrophic scars; atherosclerosis and restenosis; surgical complications; chemotherapeutic drug-induced fibrosis; accidental injury; and burns (Wynn, T. 2004: Nat. Rev. Immunol. 4(8): pp. 583-594).
Wound healing and disregulated events leading to fibrosis both involve the proliferation and differentiation of certain cell types (tissue dependent), mainly fibroblasts to myofibroblasts and the deposition of extracellular matrix. Whether the fibroblasts are locally derived or if they are coming from a circulating precursor population is unclear. Fibrocytes are a distinct population of fibroblast-like cells that derive from peripheral blood monocytes that enter site of tissue injury to promote angiogenesis and wound healing.
The ocular response to hypoxia and inflammatory insults typically leads to retinal or choroidal neovascularization. During development, this process is highly regulated and leads to the establishment of a well organized, mature vasculature. In the adult eye, this is often not the case, and associated glial cells (e.g., astrocytes, and Mueller cells), microglia and RPE cells proliferate with the endothelial cells, leading to fibrosis and scar formation. The role of cell adhesion molecules, such as integrins, in regulating the relationship between proliferating vascular cells and their environment, has been the focus of many studies (Martin Friedlander Journal of Clinical Investigation http://www.jci.org Volume 117 Number 3 Mar. 2007).
There is ample evidence indicating the involvement of alpha5 beta1 integrin and extracelluar matrix interaction during fibroblast differentiation. High expression of alpha5 beta1 integrin is found in activated fibroblasts with strong accumulation of alpha5beta1 integrin when fibroblasts switch to the fibrotic state (Thannickal 2003, J. Biol. Chem. 278, 12384). High levels of alpha5 beta1 integrin were detected in proliferating fetal RPE cells, activated ARPE-19 cells (retinal pigmental cells) and in PVR membrane in patients with proliferative vitreoretinopathy (G Zahn et al. Invest Ophthalmol Vis Sci. 2010 1028-35; Rong Li et al Inv Ophth Vis Sci 2009, 50(12) 5988-5996). Integrin alpha5 beta1 plays a key role in inducing the activation, proliferation and differentiation of pulmonary fibroblasts (PFbs), causing an increase of extra-cellular matrix synthesis during pulmonary fibrogenesis. Strong integrin alpha5 beta1 integrin expression is seen in proliferated interstitial cells with fibroblast and myofibroblast differentiation. Changes in FN were similar to that of the alpha5 beta1 integrin. Expression of alpha5 beta1, fibronectin (FN)mRNAs and their relevant proteins increase in PFbs after TGF-beta1 administration. (Wu H, et al Zhonghua Bing Li Xue Za Zhi. 1999 December; 28(6):427-31 article in Chinese). Interaction of bronchial fibroblasts with T cells increases the production of profibrogenic cytokine IL-6. In asthmatic conditions this interaction involves CD40L alpha5 beta1 integrin. T cells and structural cells crosstalk in asthma may maintain local mucosal inflammation (Loubaki L, et al Mol Immunol. 2010 July; 47(11-12):2112-8). Moreover alpha5 beta1 integrin is expressed and restricted to the myofibroblast-rich cellular areas in palmar fibromatosis (Magro G. et al Gen Diagn Pathol. 1997 December; 143(4):203-8). Activation of hepatic stellate cells (HSC) plays an integral role in hepatic fibrosis. HSC activation increases the fibronectin alpha5 beta1 integrin receptor expression and the interactions between alpha5 beta1 integrin and fibronectin increases collagen synthesis. Production of connective tissue growth factor (CCN2) is a hallmark of hepatic fibrosis and regulates integrin expression in primary culture of hepatic stellate cells (HSC) and supports HSC adhesion via its binding of cell surface alpha5 beta1 integrin (Milliano M T et al. J Hepatol. 2003; 39(1):32-7, Huang G et al J Cell Mol Med. 2011; 15(5):1087-95). Positive association between the interstitial expression of alpha5 beta1 integrin and the relative interstitial cortical volume in renal biopsies in patients with mild and severe proteinuria suggests that alpha5 beta1 integrin may play a role in the pathogenesis of chronic progressive renal diseases. The intensity of interstitial alpha5 beta1 integrin immunoexpression positively correlates with the degree of interstitial fibrosis (Wagrowska-Danilewicz M et al. Int Urol Nephrol. 2004; 36(1):81-7).
Fibrotic traction of the retina in AMD is seen after anti-VEGF treatment and fibrotic lesion in both AMD and PDR results from neovascularization. Fibrotic lesions in AMD are not treatable with anti-VEGF and AMD patients non-responders to anti-VEGF are the patients with fibrotic lesions.
Currently treatments are available for fibrotic disorders including immune suppressive drugs such as corticosteroids, and other anti-inflammatory treatments. However the mechanism involved in the regulation of fibrosis appears to be distinct from those of inflammation, and anti-inflammatory treatment are not always effective in reducing and preventing fibrosis.
The fact that PDR patients are not treatable with current anti-angiogenic therapy (anti-VEGF) and that the AMD patients who are non-responders to anti-VEGF are those that have fibrotic lesions, indicate that a significant unmet medical need still remains particularly to reduce and prevent fibrosis and control fibrotic diseases.
WO 2009/063070, WO 2010/133669 and WO 2010/133672, disclose certain quinoline compounds which are anti-angiogenic integrin aplha5beta1 inhibitors, and their use in therapy.